This is a new investigator R01 application, in response to the Program Announcement (PA-04-158) for Ancillary Studies to the Alzheimer's Disease Neuroimaging Initiative. There is a critical need for biomarkers that can detect a "signal of efficacy" in early phase clinical trials of promising disease modifying therapies for Alzheimer's disease (AD). Functional magnetic resonance imaging (fMRI) has considerable potential as a marker of acute pharmacological effects in "Proof of Concept" AD trials and as a marker of very mild cognitive impairment (MCI) in longitudinal studies of clinical progression. Our previous fMRI studies, using a face-name associative memory paradigm, have demonstrated regionally specific pharmacological effects on memory related activation in young subjects, and significant differences in the pattern of fMRI activation between normal older controls, MCI subjects and mild AD patients. In order to further validate fMRI as a potential biomarker, we will examine test-retest reliability, cross-scanner platform reproducibility, and relate fMRI activation to clinical status cross-sectionally and longitudinally in older normal controls, MCI and mild AD subjects. We will also elucidate the factors contributing to alterations in fMRI activation using advances in fMRI and other MR techniques, including 1) mixed block/event-related subsequent memory paradigms to isolate the neural correlates of successful vs. failed memory processes, 2) arterial spin labeling (ASL) perfusion MRI to examine resting cerebral blood flow and 3) high resolution structural MRI to measure atrophy. The proposed study will take place across two sites in Boston and will utilize subject selection criteria, assessment instruments, and visit timing from the main ADNI study, with minor modifications to take full advantage of fMRI capabilities. We hypothesize that memory related fMRI activation is a sensitive marker of synaptic dysfunction due to early AD pathology that will precede atrophy and alterations in resting perfusion. The proposed research will provide essential validation studies for fMRI as a biomarker in AD clinical trials, and enhance our fundamental understanding of the early pathophysiological alterations in AD. [unreadable] [unreadable] [unreadable]